Search

Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, PD-L1-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented.KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1:1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary end point was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population.Between May 5, 2016, and May 28, 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cutoff (November 30, 2020) was 45.1 months (interquartile range, 39.0-48.8). Median OS was 17.2 months (95% confidence interval [CI], 11.7-22.9) with pembrolizumab and 15.3 months (95% CI, 10.9-18.1) with chemotherapy (hazard ratio, 0.90 [95% CI, 0.67-1.19; P = 0.2262]). Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage).Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.ClinicalTrials.gov, NCT02611960.

Atezolizumab; Isatuximab; Solid tumors Atezolizumab; Isatuximab; Tumores sólidos Atezolizumab; Isatuximab; Tumors sòlids Background The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients. This work was sponsored by Sanofi (no grant number).

Background HER2/neu is overexpressed in 15-25% of gastric cancer patients and associated with poor prognosis. Treatment with recombinant monoclonal Abs against HER2/neu is effective yet alternatives are needed due to cost and global availability issues. Thus a peptide vaccine (IMU-131) was developed, consisting of 3 fused B-cell epitopes (p467) from the HER2/neu extracellular domain coupled to CRM197 and administered with the adjuvant Montanide. The present study evaluated the optimal/safe vaccine dose leading to immunogenicity and clinical responses. Methods In an open-label multicenter Phase Ib trial (SE-Asia & Eastern Europe), 14 patients with HER2/neu overexpressing ( ++/ +++) gastric adenocarcinoma were recruited to receive 3 injections of IMU-131 (days 0, 14, 35) in combination with chemotherapy (CT). Dose escalation (10, 30 and 50 µg) was performed in 3 cohorts (C) to evaluate safety, immunogenicity and clinical responses. Results No SAEs related to IMU-131 administration were reported. Eleven patients were evaluable for vaccine-specific immune responses and RECIST assessment. Higher HER2-specific IgG levels were observed in C2 (30 µg) vs. C1 (10 µg). 3/5 patients in C2 showed moderate or little increase in HER2-specific Abs, while all C3 patients (50µg) responded with moderate to high Ab levels. According to RECIST, 1 patient showed complete response, 5 partial response and 4 stable disease. Strong correlation between high Ab levels and clinical responses was observed in C3, while this was only moderate in C2. Capacity to inhibit HER2 phosphorylation was tested in patient sera and could be detected in association with strong tumor reduction. Furthermore, patients with good clinical responses, but low Ab titers featured cellular responses with high IFNγ and TNFα/IL-10 ratios. Conclusions The vaccine was well tolerated and safe with Ab responses at the highest dose showing strong correlation with clinical responses. Currently, the 50 µg dose is being evaluated in a Phase II trial with two arms (IMU 131 + CT and CT only). Clinical trial identification NCT02795988. Legal entity responsible for the study Imugene Ltd. Funding Imugene Ltd. Disclosure U. Wiedermann: Research grant / Funding (institution), Officer / Board of Directors, CSO until September 2018: Imugene; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Themis. I. Bulat: Advisory / Consultancy, Research grant / Funding (self), Full / Part-time employment: Arensia Exploratory Medicine . T. Yau: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. M. Maglakelidzde: Advisory / Consultancy, Research grant / Funding (self), Full / Part-time employment: ARENSIA Exploratory Medicine . T. Ungtrakul: Travel / Accommodation / Expenses: AstraZeneca. C.C. Zielinski: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Officer / Board of Directors, Scientific Advisory Board Member until June 2018: Imugene; Honoraria (self), Advisory / Consultancy: Ariad; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: KGaA; Honoraria (self), Advisory / Consultancy: Fibrogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Athenex. L. Chong: Honoraria (self), Advisory / Consultancy, Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Imugene Ltd. N. Ede: Leadership role, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Imugene Ltd. A. Good: Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Imugene Ltd; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Kazia Therapeutics; Shareholder / Stockholder / Stock options: Living Cell Technologies. All other authors have declared no conflicts of interest.

Background Elevated AFP in patients (pts) with HCC is associated with worse prognosis. Two placebo (P)-controlled trials (REACH, REACH-2) have studied ramucirumab (RAM, anti-VEGFR2 antibody) in pts with HCC after sorafenib, with REACH-2 enrolling only pts with baseline AFP ≥400ng/mL. In REACH-2 RAM treatment (trt) improved overall survival (OS) compared to P, consistent with REACH (AFP ≥400ng/mL) pts. Here we present post-hoc analyses assessing the prognostic and predictive value of baseline AFP in both studies. Methods Pts with HCC, Child-Pugh A, ECOG PS 0-1, and prior sorafenib were randomized to RAM 8mg/kg or P Q2W. The prognostic value of baseline AFP was assessed by Cox regression models with either continuous or dichotomous (≥400 vs Results Baseline AFP was confirmed as a significant continuous (REACH and REACH-2; p Conclusions The prognostic impact of baseline AFP is an important factor to consider in trial design. The findings suggest AFP may be predictive of RAM OS benefit. Results also confirm AFP ≥400ng/mL is appropriate selection criterion for RAM OS benefit. Clinical trial identification NCT01140347, NCT02435433. Editorial acknowledgement Nathalie Godinot, funded by Eli Lilly and Company. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure A.X. Zhu: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: Roche/Genentech. P.R. Galle: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Schering Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex Medical; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: Bristol-Meyers Squibb; Advisory / Consultancy: MSD; Honoraria (self): Sillajen. J.M. Llovet: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Celsion; Advisory / Consultancy: Incyte; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Glycotest; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Bayer Schering Pharma. R.S. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche Genentech; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Exelixis. Y. Kang: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche Genentech; Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (self): LSK Biopharma. E. Assenat: Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Terasphere; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Servier. G. Brandi: Advisory / Consultancy: Eli Lilly and Company. K. Motomura: Honoraria (self): Eisai. I. Ohno: Advisory / Consultancy: Merck Serono; Speaker Bureau / Expert testimony: Taiho Pharmaceutical. B. Daniele: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Celgene. A. Vogel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Delcath Systems; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Baxalta; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Sanofi; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD. T. Yamashita: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Eisai. C. Hsu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Taiho Pharmaceutical. T. Meyer: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Tarveda Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): BTG; Advisory / Consultancy: Beigene; Advisory / Consultancy: MSD; Research grant / Funding (institution): Bayer. R. Widau: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. W. Schelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. C. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. Y. Hsu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M. Kudo: Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Research grant / Funding (institution): AbbVie; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Gilead Sciences; Honoraria (self): Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EA Pharma; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Bristol-Myers Squibb Japan. All other authors have declared no conflicts of interest.

Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of pembrolizumab (pembro) or pembro + chemotherapy (chemo) vs EXTREME (E) as first-line therapy for recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). At the second interim analysis, overall survival (OS) was significantly longer with pembro than E in patients with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). Pembro + chemo significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Patients with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to pembro 200 mg Q3W, pembro + chemo (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + chemo) until progressive disease, unacceptable toxicity, 6 cycles of chemo, or 24 months of pembro. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with pembro vs E were 28.6% vs 76.9% in the Asia subgroup and 13.9% vs 67.2% in the non-Asia subgroup; rates with pembro + chemo vs E were 71.9% vs 76.9% in the Asia subgroup and 70.8% vs 67.2% in the non-Asia subgroup. Table: 286O Asia CPS ≥20 Asia CPS ≥1 Asia Tot Pop Non-Asia CPS ≥20 Non-Asia CPS ≥1 Non-Asia Tot Pop HR; 95% CI P vs E 22 v 23 P+C v E 22 v 21 P v E 48 v 46 P+C v E 45 v 43 P v E 56 v 53 P+C v E 57 v 49 P v E 111 v 99 P+C v E 104 v 89 P v E 209 v 209 P+C v E 197 v 192 P v E 245 v 247 P+C v E 224 v 229 OS 0.39; 0.19-0.80 0.80; 0.41-1.58 0.80; 0.51-1.27 1.13; 0.71-1.79 0.74; 0.48-1.13 1.03; 0.68-1.58 0.75; 0.54-1.04 0.68; 0.48-0.96 0.76; 0.61-0.95 0.65; 0.51-0.82 0.87; 0.71-1.06 0.71; 0.57-0.88 PFS 1.16; 0.63-2.11 1.07; 0.58-1.99 1.25; 0.82-1.91 1.14; 0.74-1.76 1.39; 0.94-2.05 1.12; 0.75-1.66 0.95; 0.70-1.28 0.65; 0.47-0.89 1.10; 0.89-1.35 0.74; 0.60-0.92 1.27; 1.05-1.54 0.82; 0.67-1.00 HRs, Kaplan-Meier method; 95% CIs, Cox regression model. Conclusions Pembro vs E showed favorable OS in Asia and non-Asia subgroups, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgroups; safety was favorable. Pembro + chemo vs E showed favorable OS in patients with CPS ≥20 in Asia and non-Asia subgroup regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, CMPP, and Holly Cappelli, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. K. Tanaka: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R-L. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia, MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim (M), Merck Serono (M), Roche (M), Eli Lilly (M), Amgen (M); Speaker Bureau / Expert testimony: Eli Lilly Inc; Research grant / Funding (self): Amgen Inc, MSD, Roche & Genetech, AstraZeneca; Travel / Accommodation / Expenses: Eisai (M), Eli Lilly (M), AstraZeneca (M), MSD Inc, Roche (M), Merck Serono (M), Mundipharma (M), Novartis (M), Pfizer (M), Amgen (M), Menarini (M). V. Sriuranpong: Honoraria (self): MSD; Advisory / Consultancy: MSD. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. N. Nohata: Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: MSD KK. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. B. Gumuscu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. R. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. M. Tahara: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. All other authors have declared no conflicts of interest.

Background KEYNOTE-048 (NCT02358031) is a randomized, open-label, phase 3 trial of P or P + chemotherapy (C) vs EXTREME (E) as 1L therapy for R/M HNSCC. At 2nd interim analysis, overall survival (OS) was significantly longer with P than E in patients (pts) with PD-L1 combined positive score (CPS) ≥20 (P = 0.0007) and CPS ≥1 (P = 0.0086) and was noninferior in the total population (pop). P+C significantly improved OS vs E in the total pop (P = 0.0034). Safety was favorable or similar to that of E. Methods Pts with R/M HNSCC not curable by local therapy and with no prior systemic therapy were randomized (1:1:1) to P 200 mg Q3W, P+C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/day for 4 days Q3W), or E (cetuximab 400 mg/m2 loading dose with 250 mg/m2 subsequent infusion QW + C) until progressive disease, unacceptable toxicity, 6 cycles of C, or 24 months of P. Primary end points were progression-free survival and OS. Data cutoff date was June 13, 2018. Results Efficacy is reported in the table. Gr 3-5 drug-related AE rates with P vs E were 28.6% vs 76.9% in the Asia subgrp and 13.9% vs 67.2% in the non-Asia subgrp; rates with P+C vs E were 71.9% vs 76.9% in the Asia subgrp and 70.8% vs 67.2% in the non-Asia subgrp. Conclusions P vs E showed favorable OS in Asia and non-Asia subgrps, regardless of PD-L1 status; responses were durable, particularly among all non-Asia subgrps; safety was favorable. P+C vs E showed favorable OS in pts with CPS ≥20 in Asia and non-Asia subgrps regardless of PD-L1 status, durable responses, and similar safety. Clinical trial identification NCT02358031. Editorial acknowledgement Doyel Mitra, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Table: 1136P . Asia, CPS ≥20 Asia, CPS ≥1 Asia, Total Population Non-Asia, CPS ≥20 Non-Asia, CPS ≥1 Non-Asia, Total Population P vs E n = 22 vs 23 P+C vs E n = 22 vs 21 P vs E n = 48 vs 46 P+C vs E n = 45 vs 43 P vs E n = 56 vs 53 P+C vs E n = 57 vs 49 P vs E n = 111 vs 99 P+C vs E n = 104 vs 89 P vs E n = 209 vs 209 P+C vs E n = 197 vs 192 P vs E n = 245 vs 247 P+C vs E n = 224 vs 229 OS: HR (95% CI ) 0.39 (0.19-0.80) 0.80 (0.41-1.58) 0.80 (0.51-1.27) 1.13 (0.71-1.79) 0.74 (0.48-1.13) 1.03 (0.68-1.58) 0.75 (0.54-1.04) 0.68 (0.48-0.96) 0.76 (0.61-0.95) 0.65 (0.51-0.82) 0.87 (0.71-1.06) 0.71 (0.57-0.88) PFS: HR (95% CI) 1.16 (0.63-2.11) 1.07 (0.58-1.99) 1.25 (0.82-1.91) 1.14 (0.74-1.76) 1.39 (0.94-2.05) 1.12 (0.75-1.66) 0.95 (0.70-1.28) 0.65 (0.47-0.89) 1.10 (0.89-1.35) 0.74 (0.60-0.92) 1.27 (1.05-1.54) 0.82 (0.67-1.00) ORR, % 22.7 vs 30.4 45.5 vs 33.3 16.7 vs 37.0 31.1 vs 37.2 14.3 vs 41.5 31.6 vs 40.8 23.4 vs 37.4 42.3 vs 39.3 19.6 vs 34.4 37.6 vs 35.4 17.6 vs 34.8 36.6 vs 35.4 Median DOR, mo 5.7 vs 4.3 6.1 vs 4.3 12.6 vs 4.3 6.1 vs 4.2 12.6 vs 4.1 5.7 vs 4.1 23.4 vs 4.1 8.5 vs 4.1 20.9 vs 4.5 6.9 vs 4.4 20.9 vs 5.0 6.9 vs 5.0 C, chemotherapy; CI, confidence interval; CPS, combined positive score; DOR, duration of response; E, EXTREME; HR, hazard ratio; mo, months; ORR, objective response rate; OS, overall survival; P, pembrolizumab; PFS, progression-free survival. HRs are from product-limit (Kaplan-Meier) method for censored data; 95% CIs are based on Cox regression model with Efron’s method of tie handling with treatment as a covariate. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure M. Tahara: Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical, MSD, AstraZeneca; Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Celgene, Amgen; Research grant / Funding (institution): Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Rakuten Medical, Novartis, Loxo, AstraZeneca, Rakuten Medical. R. Hong: Research grant / Funding (institution): MSD. W.Z. Wan Ishak: Honoraria (self): Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar; Advisory / Consultancy: Boehringer Ingelheim, Merck Serono, Roche, Eli Lilly, Amgen; Speaker Bureau / Expert testimony: Eli Lilly; Research grant / Funding (self): Amgen Inc, MSD, Roche, Genentech, AstraZeneca; Travel / Accommodation / Expenses: Eisai, Eli Lilly, AstraZeneca, MSD Inc, Roche, Merck Serono, Mundipharma, Novartis, Pfizer, Amgen, Menarini. S. Takahashi: Honoraria (self): Novartis, MDS, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca; Research grant / Funding (self): MSD, Eisai, Taiho, Chugai, Daiichi-Sankyo, Bayer, AstraZeneca, Quintiles. K. Tanaka: Honoraria (self): AstraZeneca, ONO Pharmaceutical, MSD, Eisai, Merck Serono, Bristol-Myers Squibb. N. Nohata: Shareholder / Stockholder / Stock options: Merck & Co., Inc.; Full / Part-time employment: MSD K.K. A. Roy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. B. Gumuscu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. R.F. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. N. Ngamphaiboon: Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Advisory / Consultancy: MSD, Amgen, Novartis, Boehringer Ingelheim, AstraZeneca; Speaker Bureau / Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel / Accommodation / Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho; Research grant / Funding (institution): MSD, Pfizer, Roche, AstraZeneca. All other authors have declared no conflicts of interest.

There were tumor strictures commonly encountered in the esophageal squamous cell carcinoma (ESCC) to limit the conventional echoendoscope for exact tumor staging and size measurements. This study evaluated the role of miniprobe endosonography (EUS) to predict the survival of ESCC patients after concurrent chemoradiation therapy (CCRT). This study prospectively enrolled ESCC patients to receive high-frequency miniprobe EUS for the assessments of the tumor size and tumor-node-metastasis (TNM) stage. For the patients defined with advanced stages to receive CCRT as initial therapy, the tumor size parameters assessed by EUS were analyzed for their correlation with the treatment response and the patients' survivals. Fifty-four patients, >96% with advanced TNM stage III or IV, were enrolled with a medium follow-up of 320.5 days. Almost all of the 54 cases had partial or complete stricture of the esophageal lumens due to the tumor obstructions at enrollment. The overall median survival was 18.6 months, and the 1- and the 2-year survival rates were 64.9 and 45.2%, respectively. Patients with initial tumor length 56.5 months vs. 11.5 months, P= 0.006). The patients with initial tumor length

Background: Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression. Methods: Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m−2, followed by cisplatin 30 mg m−2 infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m−2 per day plus leucovorin 90 mg per day on days 1–14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment. Results: From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22–75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41–74%) and 53% (95% CI: 38–68%), respectively. The disease control rates in these populations were 85% (95% CI: 70–94%) and 82% (95% CI: 68–92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3–4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities. Conclusion: Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) (also called VEGFR-3) is activated by its specific ligand, VEGF-C, which promotes cancer progression. The VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumours. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, activation of the VEGF-C/VEGFR-3 axis in several types of solid tumours enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis. In this review, we discuss the novel function and molecular mechanism of the VEGF-C/VEGFR-3 axis in cancer progression.

Addition of cetuximab showed trend, but not significantly, to improve the therapeutic effects of gemcitabine and oxaliplatin combination for advanced biliary tract cancer in current randomized phase II trial. The trend of improvement did not correlate with KRAS mutation status. Biomarkers finding for selecting patients who will benefit most from anti-EGFR targeted therapy is warranted. Background Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. Patients and methods ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). Results The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Conclusions Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status. Clinical Trials number This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

Background: Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours. Methods: Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course. Results: Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile. Conclusions: These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.

Group V transition metal nitride foils were fabricated in an ultrahigh vacuum chamber and superconducting transition temperature ( T c ), lattice parameter ( a 0 ), and electron energy loss (EELS) measurements were performed on these samples. It is found that as a function of increasing nitrogen-to-transition-metal atomic ratio, T c first increases with increasing nitrogen content then decreases before reaching a 1 : 1 transition metal to nitrogen stoichiometry ratio. T c also increases with increasing lattice parameter a 0 and then decreases before reaching the maximum values for a 0 which are about 4.14 A for NV x and 4.392 ± 0.002 A for NbN x . The EELS data indicate that the outermost metal d electrons transfer to nitrogen atoms during formation of transition metal nitrides. However, the possibility of electrons forming covalent bonds cannot be ruled out.

There were tumor strictures commonly encountered in the esophageal squamous cell carcinoma (ESCC) to limit the conventional echoendoscope for exact tumor staging and size measurements. This study evaluated the role of miniprobe endosonography (EUS) to predict the survival of ESCC patients after concurrent chemoradiation therapy (CCRT). This study prospectively enrolled ESCC patients to receive high-frequency miniprobe EUS for the assessments of the tumor size and tumor-node-metastasis (TNM) stage. For the patients defined with advanced stages to receive CCRT as initial therapy, the tumor size parameters assessed by EUS were analyzed for their correlation with the treatment response and the patients' survivals. Fifty-four patients,96% with advanced TNM stage III or IV, were enrolled with a medium follow-up of 320.5 days. Almost all of the 54 cases had partial or complete stricture of the esophageal lumens due to the tumor obstructions at enrollment. The overall median survival was 18.6 months, and the 1- and the 2-year survival rates were 64.9 and 45.2%, respectively. Patients with initial tumor length6 cm assessed by the pre-CCRT EUS had a better survival than those with length ≥6 cm (median survival:56.5 months vs. 11.5 months, P= 0.006). The patients with initial tumor length6 cm had a higher rate of downstage than those with tumor length ≥6 cm after the first course of CCRT (80.0% vs. 16.7%, P= 0.035). Multivariate Cox regression confirmed the initial tumor length (hazard ratio [HR]= 1.21, P= 0.034) as well as the presence of distal metastasis are both independent predictors of the survival in ESCC patients receiving CCRT. For the ESCC patients, commonly with tumor stricture, the miniprobe EUS to assess tumor length before CCRT can predict the treatment response and the survivals.

Aim: Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. Methods: Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75. Results: Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR was 0.866 (95% CI 0.717, 1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p 5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO. Conclusions: No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation. Disclosure: J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to "Instituto do Cancer do Estado de Sao Paulo" ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.

Systemic lupus erythematosus (SLE) is the most common secondary glomerulonephritis resulting in end-stage renal disease (ESRD) among young adults in Taiwan. Studies of the infectious complications and outcomes among such SLE patients undergoing peritoneal dialysis (PD) are limited.A retrospective age- and gender-matched case control study.A university teaching hospital.There were 23 SLE patients with ESRD receiving PD for more than 3 months during the past 15 years. Another 46 age- and gender-matched non-SLE nondiabetic patients receiving PD were selected as the control group in this study.All patients underwent PD as renal replacement therapy and were regularly followed up at this hospital.Technique survival and incidences of exit-site infection (ESI) and peritonitis in these patients.The SLE patients had a lower predialysis serum albumin than the control group (3.16 +/- 0.50 g/dL vs 3.52 +/- 0.50 g/dL, p0.01). The incidences of exit-site infection (ESI) and peritonitis were higher for SLE patients than for control patients (p0.01 and p0.001, respectively). Kaplan-Meier survival analysis indicated that SLE patients had shorter time intervals to first infectious complications, and poorer technique survival. Infection was the major cause of dropout and mortality in the SLE patients. The SLE patients had a reduced chance of receiving a renal transplant. The use of steroids by SLE patients was associated with a higher incidence of peritonitis (p = 0.04), but association with ESI was insignificant. In a Cox regression model, the underlying SLE was the only risk factor for technique failure and time interval to first infectious complication.SLE patients undergoing PD are more susceptible to infection than age- and gender-matched non-SLE nondiabetic patients and have poorer technique survival. Systemic lupus erythematosus itself may further compromise the immunity of uremic patients.

The disconnect twin-bag (TB) system was first introduced in Taiwan for use as an exchange system in continuous ambulatory peritoneal dialysis (CAPD) in 1995. Following its introduction, the incidence of CAPD-associated peritonitis declined, but the incidence of exit-site infection (ESI) increased. To determine the cause of the increase in ESI incidence after the introduction of the TB system, this study compared the incidence of ESI among patients using the O set, ultraviolet antiseptic (UV) device, and the TB system.A total of 170 patients who had received CAPD for more than 3 months were enrolled in this study. Poisson test and Kaplan-Meier survival analysis were used to compare the ESI incidence and ESI-free catheter survival among patients using the O set, UV device, or TB system. Cox stepwise forward proportional hazard analysis was used to assess the impact of sex, education, cause of uremia, age, and type of exchange system on ESI.The incidences of ESI differed significantly among patients using the three exchange systems, with 20.9, 13.8, and 4.0 episodes per 100 patient-years for patients using the TB system, O set, and UV device, respectively. New patients using the TB system also had a shorter mean interval of ESI-free catheter survival than those using the UV device (26.9 vs 58.8 months, p = 0.002). In the Cox stepwise forward proportional hazard analysis, non-lupus patients had a lower risk of developing ESI than lupus patients (relative risk [RR] 0.40, p = 0.03). The RR of ESI in patients using the UV device was also lower than in those using the TB system (RR 0.15, p0.01).In this study, use of the TB system was associated with a higher incidence of ESI. The increased ESI incidence may be related to the heavier mini-transfer set of the TB system. Therefore, special attention should be given to fastening the mini-transfer set tightly during the exchanging procedure to prevent traction on the exit-site, which is associated with an increased incidence of subsequent ESI.

Open architecture technology is ushering in new advances in the world of computer numerically controlled machines. Yet, some major benefits of open architecture technology have failed to materialized due to the lack of a standard open architecture specification. We propose an open architecture framework to fill the specification void. The proposed framework supports component-based technology by specifying a control class hierarchy, plug-and-play components and a design framework. This framework can be used to build applications ranging from a single-axis device to a multi- arm robot. An example application applying the framework is documented.

Prevention of the development of end-stage renal disease is one of the most promising areas of research in nephrology. Because mesangial cell proliferation and extracellular matrix accumulation have been regarded as antecedents of glomerulosclerosis, agents that can inhibit mesangial cell proliferation may have a potential to retard the progression of renal diseases. Therefore, we investigated several clinically available agents that might affect mesangial cell proliferation and collagen synthesis in male Sprague-Dawley rats. Cell proliferation was measured by the tetrazolium dye uptake method. Collagen synthesis was measured by 3H-proline incorporation into pepsin-resistant, salt-precipitated collagen. Intracellular cAMP levels were measured by enzyme immunoassay. Our results showed that hydralazine (82% inhibition at 10 micrograms/mL), ticlopidine (61% inhibition at 30 micrograms/mL), aminophylline (66% inhibition at 200 micrograms/mL), and nicametate (91% inhibition at 1 mg/mL) inhibited serum-stimulated rat mesangial cell (RMC) growth in a dose-dependent manner. Ticlopidine (43% inhibition at 30 mg/mL), aminophylline (52% inhibition at 200 mg/mL), and nicametate (35% inhibition at 1 mg/mL) inhibited collagen synthesis in confluent RMCs. Aminophylline may act through increasing intracellular cAMP levels (9.7 +/- 0.7 pmol/mg protein at 200 micrograms/mL of aminophylline vs 4.2 +/- 0.6 pmol/mg protein at control). These data suggest that aminophylline, ticlopidine, hydralazine, and nicametate can inhibit RMC proliferation and collagen synthesis.

General Motors Powertrain Group (GMPTG) has been the leader in implementing open, modular architecture controller (OMAC) technologies in its manufacturing applications since 1986. The interest in OMAC has been greatly expanded for the past two years because of the advancement of personal computer technologies and the publishing of the OMAC whitepaper by the US automotive companies stating the requirements of OMAC technologies in automotive applications. The purpose of this paper is to describe the current OMAC projects and the future direction of implementation at GMPTG. An overview of the OMAC project and the definition of the OMAC concept are described first. The rationale of pursuing open technologies is explained from the perspective of GMPTG in lieu of its agile manufacturing strategy. Examples of existing PC-based control applications are listed to demonstrate the extensive commitment to PC-based technologies that has already been put in place. A migration plan form PC-based to OMAC-based systems with the thorough approach of validation are presented next to convey the direction that GMPTG is taking in implementing OMAC technologies. Leveraged technology development projects are described to illustrate the philosophy and approaches toward the development of OMAC technologies at GMPTG. Finally, certain implementation issues are discussed to emphasize efforts that are still required to have successful implementations of OMAC systems.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A total of 227 patients with renal failure requiring acute haemodialysis with placement of a total of 260 Medcorp double lumen catheters at National Taiwan University Hospital from July 1992 to July 1993 were reviewed. Among them, only 135 patients receiving a total of 168 catheter placements and a complete infectious work-up were selected for this study. The mean age of the patients was 55 years (range 15-89 years); 63 (46.7%) were male and 75 (53.3%) were female. The three major reasons for dialysis were chronic glomerular disease (CGN; 49%), diabetic nephropathy (13%) and nephritis associated with systemic lupus erythematosus (SLE; 11%). The catheters remained in place for an average of 27.8 days (9-73 days) and each catheter was used for an average of eight treatments (2-26). The reasons for catheter removal were classified as: availability of permanent vascular access (48%), recovery of renal function (10%), scheduled duration (30 days, not every case; 4%), expiration of patient (10%), suspicion of catheter-related infections (15%), and catheter thrombosis/occlusion (9%). Seven cases with local haematoma and one case of pneumothorax were also identified (total 5%). In total, a 21.4% catheter-related infection rate was observed and micro-organisms such as Staphylococcus aureus (33%), coagulase-negative staphylococci (36%) and Enterococcus (19%) were isolated. The cumulative probability of patients remaining free from catheter-related infections was about 75% by the end of the fourth week post-catheter insertion, and decreased to less than 50% near the end of the second month of persistent catheterization.(ABSTRACT TRUNCATED AT 250 WORDS)

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Background Gastrointestinal stromal tumor (GIST) is a mutant oncoprotein c-Kit droved cancer. Patients suffered drug resistance after prolonged standard treatment of tyrosine kinase inhibitor (TKI), imatinib mesylate (IM). Inhibition of heat-shock protein 90 (Hsp90), a chaperone responsible for protein maturation and stability, causing its client proteins degradation, as c-Kit, is a developing therapy for cancer. However, the mechanisms of Hsp90 inhibition-induced c-Kit downregulation in post-translational and transcriptional levels have rarely been investigated. Methods and results Our data showed that NVP-AUY922 (AUY922), a new class of Hsp90 inhibitor, inhibited the growth of GIST882 and GIST48 cells with mutant c-Kit protein expression that was accompanied with reduction of both total and phosphor-c-Kit protein and induction of apoptosis. Pharmacological inhibition on either autophagy or proteasome degradation pathway could partially reverse endogenous c-Kit turnover and AUY922-induced c-Kit reduction. These findings were further confirmed by the co-localization of c-Kit with either LC-3B or acridine orange-labeled autophagosome in confocal microscopy, and delay of c-Kit degradation by silencing autophagosome essential Beclin-1 protein. In addition, AUY922 could also reduce c-Kit mRNA without affecting its degradation. Our preliminary data showed that activities and nuclear levels of several transcription factors in GIST cells were diminished after AUY922 treatment. DNA affinity precipitation assay and chromatin immunoprecipitation (ChIP) will be performed to validate the binding of the candidate transcript factors on the c-Kit promoter. Conclusions This is the first report showing the involvement of autophagy in endogenous as well as Hsp90 inhibitor-induced c-Kit degradation. Moreover, AUY922 treatment resulted in downregulation of c-Kit through protein degradation and transcriptional mRNA regulation in GIST cells. These findings address the mechanisms of AUY922 on c-Kit protein downregulation and highlight the potential use of AUY922 in TKI-refractory, c-Kit-expressing GIST. Disclosure All authors have declared no conflicts of interest.

86 Background: Cisplatin-HDFL, consisting of weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil (5-FU) and leucovorin (LV), is an effective and low-toxicity regimen for patients with advanced gastric cancer (GC) in Taiwan (J Clin Oncol. 1994;12(4):875; J Clin Oncol. 2006;24(18S):A14063). Everolimus (RAD001), a derivative of rapamycin, is an orally bioavailable mTOR inhibitor. We have demonstrated that low-dose everolimus (0.5-5.0 nM) sensitizes cytotoxic effects of cisplatin and 5-FU in GC cells (Proc Am Assoc Cancer Res. 2007;48:A4043). Methods: Patients who had pathologically confirmed chemonaive advanced GC, at least 1 measurable lesion, a fasting serum triglyceride level > 70 mg/dl, ECOG PS 0-2, and adequate organ functions were treated with everolimus 10 mg po on days 1, 8, and 15 concurrently with the initiation of chemotherapy; cisplatin 35 mg/m2 iv 24h infusion on days 1 and 8; 5-FU 2,000 mg/m2 and LV 300 mg/m2 (HDFL) iv 24h infusion on days 1, 8, and 15, in a every 28-day cycle. Response assessment was performed every 2 cycles. The primary endpoint was confirmed objective response rate (RR) by RECIST. Results: Between March 2008 and July 2010, 24 patients (M:11, F:13) with a median age of 53 (range: 33-69) were evaluable for response. The overall RR was 50% (95% CI: 29-71%) with 12 partial responders. Among a total of 162 cycles (median: 7, range: 1-13) given, grade (Gr) 3/4 toxicities included neutropenia (4.3%), infection (2.5%), nausea (3.1%) and vomiting (3.1%). Gr 1/2 nausea, vomiting, stomatitis, and diarrhea developed in 19.2%, 15.4%, 14.8%, and 5.5% of cycles, respectively. Skin rash and hand-foot syndrome were mild. One patient developed reversible HDFL-related hyperammonemic encephalopathy. Median progression-free survival was 8.4 months (range: 1.3-15.4+) and median overall survival was 14.8 months (range: 4.0-21.6+). Conclusions: Weekly low-dose everolimus plus weekly cisplatin-HDFL is an effective first-line regimen for patients with advanced GC. Addition of weekly low-dose everolimus to infusional cisplatin-HDFL did not add gastrointestinal toxicities. No significant financial relationships to disclose.

Kengyilia guidenensis, a new species from western China, is described and illustrated. Cytological observations are provided, and comparisons with similar species are made. During an expedition to western China, a new species of Kengyilia was found. It was growing on a mountain slope close to the highway from Guide to Guomaying, between the 150 and 151 Km road poles. When collected it was identified as K. nana J. L. Yang, Yen & Baum; however, the habitat of K. nana is alpine steppes above 4000 m, whereas the Guide population was found just below 3100 m altitude and in stony slopes. The habitat of the Guide population is similar to that of K. kokonorica (Keng) J. L. Yang, Yen & Baum, but differs by being dwarf in appearance and by having ovate, dense, small spikes. In the same site another species of Kengyilia was found. This was K. mutica (Keng ex Keng & S. L. Chen) J. L. Yang, Yen & Baum, from which it readily differs in gross morphology by its dwarf habit and by its short ovate spike with long lemma awn. Kengyilia mutica does not have awns, and its spike is long and cylindrical. These preliminary observations led to the suspicion that a new species was on hand. The purpose of the present paper is to describe this species and to detail differences from the species most similar to it. MATERIALS AND METHODS Herbarium specimens and seeds were collected in 1993 in Guide County, Qinghai Province, China, and compared with specimens of Kengyilia nana and K. kokonorica (including their types) in N and SAUTI. Cytological observations were made using the methods detailed in Yen and Yang (1990). DESCRIPTION Kengyilia guidenensis Yen, J. L. Yang & Baum, sp. nov. TYPE: China. Qinghai Province: Guide County, Guide to Guomaying highway between markers 150 and 151 Km, alt. 3100 m, 35089'N, 100026'E, 11 Sep. 1993, C. Yen, J. L. Yang & G. L. Sun 930001 (holotype, SAUTI; isotype, DAO). Figure 1. Kengyiliae kokonoricae (Keng) J. L. Yang, Yen & Baum affinis, sed laminis superioribus albo-villosis; spicis brevioribus, 3-3.5 cm, et angustioribus, 5 mm; spiculis brevioribus, 7 mm, et plurifloribus, 5-7; glumis longioribus, 4-7 mm, lanceolatis; aristis lemmatum brevioribus, 1.54 mm; carinis palearum ominino ciliatis; antheris longioribus, 3 mm, differt. Kengyiliae nanae J. L. Yang, Yen & Baum affinis, sed culmis longioribus, 35-50 cm longis; foliorum vaginis glabris, laminis longioribus, 8.5-9 cm longis; spicis angustioribus, 5 mm latis; glumis lanceolatis; aristis lemmatum brevioribus, 1.5-4 mm longis; paleis ominino ciliatis differt. Caespitose perennial, with fibrous roots (Fig. lA). Culms caespitose, erect, 35-50 cm tall, 1.5 mm diam., 2-3-noded, pubescent just below the spike for 1-3 cm, geniculate at the base. Leaf sheaths glabrous, rarely pubescent in the lowermost sheaths; ligules scarious, membranous, truncate, premorse, ca. 0.5 mm long; leaf blades flat or slightly involute, narrowly lanceolate, 8.5-9 cm long, 3 mm wide, their adaxial surface with dense 1-mm-long white hairs emerging from the lateral nerves, their abaxial surface glabrous; leaf blades of the tillers densely pubescent, up to 12 cm long. Spikes erect, short and dense, ovate, 3-3.5 cm long, 5 mm wide; rachis internodes 1.5-2 mm long, densely white-pilose; spikelets oblong-ovate (Fig. 1J), greenish purple, with 5-7 florets 7 mm long (excluding awns); rachilla internodes 1-1.2 mm long, densely hirtulous; glumes unequal, wide lanceolate, w th herbaceous membranous margins (Fig. 1B, C), 1(-3)-nerved, with midrib pronounced and NOVON 5: 395-397. 1995. This content downloaded from 157.55.39.156 on Wed, 14 Jun 2017 18:06:19 UTC All use subject to http://about.jstor.org/terms

Roegneria tridentata is described and illustrated, and its karyotype is characterized. Roegneria tridentata was discovered during our fieldwork in 1992 in the Qi-lain Mt. on the northern border of Qinghai province, China. A few weeks later, it was collected in the A'Nyemaqen Mt. The two localities are more than 400 km apart. Roegneria tridentata Yen & J. L. Yang, sp. nov. TYPE: China. Qinghai: Wenquan, Xinhai, km 337 on highway 214, rocky slope, 3,750 m, 19 Sep. 1992, J. L. Yang et al. no. 9202014 (holotype, Sichuan Agricultural University Triticeae Institute; isotype, MO). Figure 1. Herba perennis caespitosa. Culmi 42-65 cm alti. Laminae 5-7 cm longae, ca. 2 mm latae, inferne glabrae, superne adpressae dense pubescentibus in projectis nervis. Spicae 5-11.5 cm longae, spiculae solitariae, 10-13 mm longae, 4vel 5-florae; glumae oblongae vel oblongoellipticae, primae 4-5 mm longae, secundae 5-6.5 mm longae, glabrae; lemmata oblongo-lanceolata, (7-)8-9 mm longa, primo 9 mm longo, 5-nervia, apicies truncati et tridentati, dentes ca. 0.5 mm longi, saepe nervo medio prominente in 0.5-1 mm longo mucronem producta; paleae apice truncatae, inter carinas scabrae, ad carinas '//2 superiore setuloso-ciliata. Herbs perennial. Culms caespitose, erect or slightly procumbent, geniculate at base, 42-65 cm tall, ca. 1.5-2 mm diam., with 2 or 3 nodes, smooth, glabrous. Leaf sheaths glabrous, persistent basal ones 2-4 cm long; ligule scarious, truncate premorse, ca. 0.5 mm long; blades involute or subinvolute, 57 cm long, ca. 2 mm broad; tillers narrowly linear, usually to 20 cm long, glabrous beneath, appressed densely pubescent on projecting veins of upper surface. Spikes erect, purple or greenish purple, 511.5 cm long, ca. 5 mm broad, with 6-14 spikelets; upper rachis internodes 5-10 mm long, the lower 15-20 mm, both glabrous, hirsute on angles; spikelets solitary, 10-13 mm long, ca. 2 mm broad, with 4 or 5 florets; rachilla internodes appressed puberulent, 1.5-2 mm long; glumes oblong or oblongelliptic, unequal, apically rounded-obtuse, rarely acute, slightly oblique; first glume 4-5 mm long; second glume 5-6.5 mm long, with 3(-5) projected veins, glabrous, sometimes sparsely short spinulose on veins; lemmas oblong-lanceolate, (7-)8-9 mm long, 5-veined, appressed white pubescent on lateral and lower parts, apically truncate and 3-toothed, the teeth ca. 0.5 mm long, sometimes midvein extending into a mucro to 0.5-1 mm long; callus obtuse, puberulent on the sides; paleas shorter to longer than lemmas, apically truncate, scabrous between keels, setulous-ciliate on upper '/3 -l/ of keel; anthers black, ca. 2 mm long. Chromosome number: 2n = 6x = 42 (Fig. 2). The characteristic awnless, 3-toothed lemmas (Fig. Ic) readily distinguish the species from other members of Roegneria C. Koch and from members of related genera. Root tips of young seedlings (ca. 2.5 cm long) were collected at 10:00 A.M. and placed in water at 3-40C for 24 hours. They were transferred to 20 ml 0.01% colchicine solution with 5 drops of dimethyl-sulfoxide and kept for 3 hours before fixation in Carnoy's fluid for 24 hours. Root tip cells were dissociated by 1N HCl for 8 minutes at 60?C, and slides were prepared by the standard acetocarmine squash method. Chromosomes were studied at diakinesis, photographs were taken by computerFigure 1. Roegneria tridentata Yen & J. L. Yang (holotype). -A. Plant. -B. Dorsal view of a floret showing 3-toothed apex of lemma and tip of longer palea. -C. Dorsal view of lemma. -D. Ventral view of floret. -E. Lodicule. -F. Dorsal view of caryopsis. -G. Ovary and stigma. -H. Stamen. -I. First glume. -J. Second glume. -K. Spikelet. NOVON 4: 310-313. 1994. This content downloaded from 207.46.13.127 on Fri, 14 Oct 2016 04:18:32 UTC All use subject to http://about.jstor.org/terms